Traumatic brain injury (TBI) is an enormous public heath problem; however, targeted therapies are lacking. After severe TBI, ischemia and energy failure frequently occur. Adenosine is a purine nucleotide that acts as a powerful endogenous neuroprotectant during ischemia-induced energy failure by decreasing neuronal metabolism and increasing cerebral blood flow (CBF), among other mechanisms. These effects are mediated through interaction of adenosine with specific receptors. The synergistic effects of increasing CBF and decreasing metabolism suggest an important neuroprotectant role for adenosine after TBI, particularly during secondary insults. Further augmenting the effects of adenosine in brain may reduce neuronal damage. Two strategies to achieve this are particularly relevant to TBI and this application, namely, 1) the inhibition of adenosine metabolism or 2) the local administration of adenosine analogs. Defining four Specific Aims, we will use an established rat model of TBI and applying cerebral microdialysis, contemporary MRI tools, functional outcome testing, and histology, we will first determine the magnitude of the adenosine response (brain interstital levels of adenosine and purine degradation products) to experimental TBI. We will then examine effects of these two defined strategies of augmenting adenosine effects both on key mechanisms of secondary damage (excitotoxicity [brain interstitial levels of glutamate, CBF by perfusion MRI, and Ca++ accumulation in brain by Mn++-contrast-enhanced MRI) and both functional and histopathological outcome. Finally, in a fifth Specific Aim, we will bridge bench to bedside by using cerebral microdialysis methods to define the participation of adenosine (and its relationship to CBF and excitotoxicity) after severe TBI in humans, during the application of contemporary therapeutic interventions (CSF drainage, mannitol, hyperventilation, and barbiturates) in the treatment of intracranial hypertension. If successful, these studies will set the stage for a clinical trial, and provide important mechanistic information on the role of adenosine after TBI in humans.